Our long-term goal is to gain a molecular understanding of the mechanisms that regulate the development and function of glutamatergic synapses in the mammalian brain. Most glutamatergic synapses share certain features, such as the presence of postsynaptic AMPA and NMDA receptors. At the same time, there is great diversity in the structure and function of glutamatergic synapses depending on the identity of the pre- and postsynaptic neuron. For example, CA3 neurons in the hippocampus receive highly facilitating mossy fiber synapses from Dentate Gyrus (DG) axons on specialized spines, called thorny excrescences. The same neurons receive association/commissural (A/C) neuron synapses on classical spines that are not highly facilitating. The CA3 A/C synapses share many structural features and functional properties with CA3-CA1 Schaffer collateral synapses, suggesting that they may be specified by common molecular mechanisms. Our preliminary studies suggest that the leucine rich repeat containing transmembrane protein LRRTM2 plays a critical role in regulating glutamatergic synapses in the hippocampus. In this proposal we wish to determine if LRRTM2 regulates specific classes of glutamatergic synapses in the hippocampus, and whether it regulates synapse structure and function in vivo. PUBLIC HEALTH RELEVANCE: The goal of this project is to understand the role of a class of cell surface proteins in the establishment and function of excitatory synaptic connections. Several childhood neurological disorders, such as Autism, Rett Syndrome, and X-linked mental retardation are characterized by defects in synaptic connectivity and function. The findings of this project should guide efforts to better understand and develop therapeutic strategies for these disorders.